The mammalian brain shows a remarkable capacity for continued neurogenesis throughout life. This feature normally occurs in two brain regions, the dentate gyrus of the hippocampus and in the olfactory system. Interestingly, it has been found that multiple forms of neural activity affect the rates of proliferation, survival, and synape formation of newborn neurons. Exercise, learning, and exposure to enriched sensory environments promote continued neurogenesis and circuit formation, whereas stress, sensory deprivation, and certain neuropathologies negatively influence neuronal division, circuit integration, and survival. Although much has been learned about the environmental and molecular factors that influence continued neurogenesis in the mammalian brain, key information regarding the cellular origins and distinct types of inputs that are made onto newborn neurons during periods of circuit formation is lacking. Neural activity is conferred through the repertoire of inputs that newborn neurons receive during their development. To date, the exact patterns of synaptic connectivity, timing of synapse formation, identity of the cel types that provide presynaptic input, and the nature of the synaptic cues onto postnatal-born neurons remain unknown. Revealing the identity and nature of these inputs is essential if we are to harness the mechanisms of continued neurogenesis for adult brain repair. The Specific Aims of this research proposal are to: 1) determine the identity and signaling nature of cells that provide presynaptic input to newborn neurons, and 2) determine the effect of enhanced presynaptic input on newborn neuron circuit integration. This proposal outlines experimentation that will combine novel molecular genetic approaches to mark, map, and manipulate the presynaptic inputs that are made onto newborn neurons in the mouse olfactory system, asking: what are the cellular origins and nature of activity cues that facilitate and promote continued circuit formation in the mammalian brain? The main objective of this proposal is to identify the cell types that provide presynaptic input onto postnatal- born neurons, and to determine their function in guiding synapse and circuit formation. Long-term, elucidating the molecular factors critical for integration of newborn neurons into circuits will significantly enhance our mechanisti knowledge of the programs that guide adult brain wiring, providing novel insights into possible avenues for cell or circuit-based brain repair. PUBLIC HEALTH RELEVANCE: Through ongoing neurogenesis, the mammalian brain is naturally endowed with a notable capacity for cellular and structural plasticity. Elucidating the molecular mechanisms that underlie the addition of newborn neurons into brain circuits holds great promise towards developing novel therapeutic approaches for repairing damaged or diseased nervous tissue.